This is a continuation application of our very successful Morris K. Udall Parkinson Disease Research Center of Excellence, seeking to identify genes that contribute to risk of developing PD. Four projects and two cores are proposed. Project I, "Candidate genes and complex interactions in PD," continues the association studies of potential susceptibility genes with PD, derived from biological candidates and the gene expression studies of Project II. Additional specific aims are gene-gene and environmental-gene interactions. Project II, "Expression Analysis and Genomic Convergence," continues and extends our expression studies of tissue obtained by our autopsy program by adding examination of the putamen and the anterior olfactory nucleus to the SN, as well as using Laser Capture Microscope to investigate specific cell types. Genes identified in project II will be tested for association in collaboration with Project I. Project III, "Mitochondrial genetics and PD," builds upon our finding of a highly significant association of mitochondrial-encoded proteins with PD, specifically the haplogroups J and K and SNP 10398, which lies in the complex I subunit ND3. Using cybrids, it looks for functional differences associated with these different mitochondrial haplogroups. It also will examine nuclear mitochondrial genes with significant differential expression in Project II for association with PD. Project IV, "Association Mapping in PD Linkage Regions," will identify PD genes in regions of linkage on chromosomes 5, 8, and 9 through a new approach, genomic "iterative" association mapping, using a new DNA pooling strategy. Once the strongest region of association is identified, haplotype-tagging will be utilized to fine map the region further. Genes lying in the region will be tested for association with PD. The projects depend heavily on our productive cores. In Core B we continue our very successful collection of PD patients and siblings, as well as our prospective autopsy program. Core C provides neuropathology support for investigation and diagnoses of autopsy material, brain banking and genotyping support for the projects. We believe that by utilizing these different but integrated approaches and resources we will be able to define the genetic contributions to PD.